17 Rizig, Mie Bandres-Ciga, Sara Makarious, Mary B Ojo, Oluwadamilola Omolara Crea, Peter Wild Abiodun, Oladunni Victoria Levine, Kristin S Abubakar, Sani Atta Achoru, Charles Obiora Vitale, Dan Adeniji, Olaleye Akinmola Agabi, Osigwe Paul Koretsky, Mathew J Agulanna, Uchechi Hall, Deborah A Akinyemi, Rufus Olusola Xie, Tao Ali, Mohammed Wulgo Shamim, Ejaz A Ani-Osheku, Ifeyinwa Padmanaban, Mahesh Arigbodi, Ohwotemu Michael Standaert, David G Bello, Abiodun Hamzat Dean, Marissa N Erameh, Cyril Oshomah Elsayed, Inas Farombi, Temitope Hannah Okunoye, Olaitan Fawale, Michael Bimbola Billingsley, Kimberley J Imarhiagbe, Frank Aiwansoba Jerez, Pilar Alvarez Iwuozo, Emmanuel Uzodinma Baker, Breeana Komolafe, Morenikeji Adeyoyin Malik, Laksh Nwani, Paul Osemeke Daida, Kensuke Nwazor, Ernest Okwundu Miano-Burkhardt, Abigail Nyandaiti, Yakub Wilberforce Fang, Zih-Hua Obiabo, Yahaya Olugbo Kluss, Jillian H Odeniyi, Olanike Adedoyin Hernandez, Dena G Odiase, Francis Ehidiamen Tayebi, Nahid Ojini, Francis Ibe Sidranksy, Ellen Onwuegbuzie, Gerald Awele D'Souza, Andrea M Osaigbovo, Godwin Osawaru Berhe, Bahafta Osemwegie, Nosakhare Reed, Xylena Oshinaike, Olajumoke Olufemi Leonard, Hampton L Otubogun, Folajimi Morenikeji Alvarado, Chelsea X Oyakhire, Shyngle Imiewan Ozomma, Simon Izuchukwu Samuel, Sarah Chabiri Taiwo, Funmilola Tolulope Wahab, Kolawole Wasiu Zubair, Yusuf Agboola Iwaki, Hirotaka Kim, Jonggeol Jeffrey Morris, Huw R Hardy, John Nalls, Mike A Heilbron, Karl Norcliffe-Kaufmann, Lucy Network, Nigeria Parkinson Disease Research Africa, International Parkinson's Disease Genomics Consortium Black Group, African American Connections to Parkinson's Disease Study Team, 23andMe Research Blauwendraat, Cornelis Houlden, Henry Singleton, Andrew Okubadejo, Njideka Ulunma Program, Global Parkinson's Genetics Okubadejo, Njideka Ojo, Oluwadamilola Abiodun, Oladunni Achoru, Charles Agabi, Osigwe Agulanna, Uchechi Akinyemi, Rufus Ali, Mohammed Ani-Osheku, Ifeyinwa Arigbodi, Ohwotemu Bello, Abiodun Erameh, Cyril Farombi, Temitope Fawale, Michael Imarhiagbe, Frank Iwuozo, Emmanuel Komolafe, Morenikeji Nwani, Paul Nwazor, Ernest Nyandaiti, Yakub Obiabo, Yahaya Odeniyi, Olanike Odiase, Francis Ojini, Francis Onwuegbuzie, Gerald Osaigbovo, Godwin Osemwegie, Nosakhare Oshinaike, Olajumoke Otubogun, Folajimi Oyakhire, Shyngle Ozomma, Simon Samuel, Sarah Taiwo, Funmilola Wahab, Kolawole Zubair, Yusuf Gams Massi, Daniel Gueumekane Bila Lamou, Eric Njamnshi Nfor, Leonard Magnerou, Mélanie Annick Fogang Fogoum, Yannick Shalash, Ali El-FawaI, Hassan Khedr, Eman Fawi, Gharib A Eltantawi, Mohamed Salama, Mohamed El-Jaafary, Shaimaa Hamed, Sharifa Tafesse Mengesha, Abenet Alemayehu Ayele, Biniyam Melka Oda, Dereje Zenebe Zewde, Yared Debebe Gelan, Yohanesse AkpaIu, Albert Charway-Felli, Augustina Stephen Sarfo, Fred Adjei, Patrick Obese, Vida Bocoum, Abdoulaye Koita, Abdou Oumar Guinto, Cheick Coulibaly, Toumany Maiga, Youssoufa Kone, Zaynab Bell, Abiodun Agabi, Osigwe Adebowale, Akintunde A Akpekpe, John Lyagba, Alagoma Wulgo, Ali Mohammed Ani-Osheku, Ifeyinwa Arabambi, Babawale Achoru, Charles Agu, Christian Erameh, Cyril Iwuozo, Emmanuel Nwazor, Ernest Fawale, Michael Otubogun, Folajimi Odiase, Francis Dike, Franklin Ishola, Ismail Wahab, Kolawole Abiodun, Kehinde Komolafe, Morenikeji Okubadejo, Njideka Obiabo, Yahaya Arigbodi, Ohwotemu Oshinaike, Olajumoke Osemwegie, Nosakhare Ekenze, Oluchi Ojo, Oluwadamilola Agabi Osigwe, Paul Nwani, Paul Balarabe, Salisu Abubakar, Sani Williams, Uduak Abiodun, Oladunni Zubair, Yusuf Fall, Maouly Mamadou Diop, Alassane Hilaire Dominique, Ewodo Touna Mochan, Andre Modi, Girish Dindayal, Saiesha Ali Awadelkareem, Eman Elsayed, Inas Dahawi, Maha Awadelkareem, Mosab Ali Misbah, Sarah Mushengez, Brighton Kimambo, Henrika Msango, Leonard Adebayo, Philip OKeng, Kigocha Diekker, Marieke URassa, Sarah Gouider, Riadh Ben Djebara, Mouna Gargouri, Amina Kacem, Imen Nasri, Amina Mrabet, Saloua Sghaier, Ikram Mkada, Imen Atadzhanov, Masharip Chishimba, Lorraine Rizig, Mie Jama, Fatumah Okunoye, Olaitan Hardy, John Houlden, Henry Singleton, Andrew Nalls, Mike Shamim, Ejaz Jonas, Cabell Williamson, Jared Hall, Deborah A Rosenbaum, Marc Davis, Staci Dean, Marissa Cromer, Candace Smith, Jenna Ruffrage, Lauren Richardson, Joseph Sipma, Rebeka Xie, Tao Padmanaban, Manesh Warren, Natalie Mercado, Tomas Disbrow, Elizabeth Chauppeta, Brian Thomas-Dean, Fermine Toms, Jamie Lofton, Katelyn Rawls, Ashley Rizer, Kyle Black, Nieci Solle, Justin O'Grady, Alyssa Sherer, Todd Fiske, Brian Başak, A Nazlı Tan, Ai Huey Noyce, Alastair Akpalu, Albert Espay, Alberto Martínez-Carrasco, Alejandro Medina, Alex Zimprich, Alexander Brice, Alexis Karimova, Altynay Hernandez, Alvaro O'Grady, Alyssa Illarionova, Anastasia Quattrone, Andrea Singleton, Andrew B Sobering, Andrew K Vinuela, Angel Sanyaolu, Arinola Schumacher-Schuh, Artur F Kishore, Asha Ahmad-Annuar, Azlina Al Mubarak, Bashayer Tang, Beisha Pizarro Galleguillos, Benjamin Jeon, Beomseok Siddiqi, Bernadette Casey, Bradford Fiske, Brian Mollenhauer, Brit Jonas, Cabell Carroll, Camille Rieder, Carlos Pantazis, Caroline B Comart, Charisse Lin, Chin-Hsien Klein, Christine Bale, Claire Shepherd, Claire E Wegel, Claire Blauwendraat, Cornelis Vitale, Dan Martinez-Ramirez, Daniel Hall, Deborah Hernandez, Dena Kp, Divya Nguyen, Duan Fon, Edward A Dadiotis, Efthymios Shamim, Ejaz Riley, Ekemini Iakovenko, Elena Stafford, Ellie Gatto, Emilia M Valente, Enza Maria Vollstedt, Eva-Juliane Faghri, Faraz Genc, Gencer Xiromerisiou, Georgia Hadjigorgiou, Georgios Hiu-Fai Chan, Germaine Arboleda, Gonzalo Kaishibayeva, Gulnaz Höglinger, Günter Leonard, Hampton Madoev, Harutyun Houlden, Henry Iwaki, Hirotaka Chen, Honglei Wu, Hsiu-Chuan Shang, Huifang Morris, Huw R F Mata, Ignacio Keller Sarmiento, Ignacio Juan Dagklis, Ioannis Tarnanas, Ioannis Aasly, Jan O Hoenicka, Janet Williamson, Jared Corvol, Jean-Christophe Foo, Jia Nee Guo, Jifeng Junker, Johanna Hardy, John Carr, Jonathan Kim, Jonggeol Jeff Orozco, Jorge Jankovic, Joseph Shulman, Joshua Hunter, Julie Solle, Justin C Murphy, Kaileigh Nuytemans, Karen Kieburtz, Karl Lohmann, Katja Marek, Kenneth Mok, Kin Ying Kumar, Kishore Levine, Kristin Chahine, Lana M Lange, Lara M Pihlstrøm, Lasse Screven, Laurel Stefanis, Leonidas Shulman, Lisa Marsili, Luca Parnetti, Lucilla Kuhl, Maggie Funayama, Manabu Sharma, Manu Tan, Manuela Kauffman, Marcelo Miranda, Marcelo Bustamante, Maria Leonor Stamelou, Maria Periñan Tocino, Maria Teresa Cornejo-Olivas, Mario Dean, Marissa Jimenez Del Rio, Marlene Makarious, Mary B Atadzhanov, Masharip Koretsky, Mathew Rodriguez-Violante, Mayela Ellis, Melina Avenali, Micol Rizig, Mie Rentería, Miguel E Inca-Martines, Miguel Z Nalls, Mike A Ibrahim Norlinah, Mohamed Salama, Mohamed Umair, Muhammad Ip, Nancy Louie, Naomi Cheung, Nelson Yuk-Fai Mencacci, Niccolò Emanuele Wood, Nicholas Williams, Nigel Okubadejo, Njideka Hattori, Nobutaka Abdul Murad, Nor Azian Ibrahim, Norlinah Mohamed Okunoye, Olaitan Ojo, Oluwadamilola Monchi, Oury Öztop Çakmak, Özgür Öztop Çakmak, Patricio Öztop Çakmak Lewis, Patrick Alfryn Pastor, Pau Reyes-Pérez, Paula Saffie Awad, Paula Chana, Pedro Chan, Phillip Kung, Pin-Jui Chan, Piu Pal, Pramod Lingappa Kukkle, Prashanth Ojha, Rajeev Kaiyrzhanov, Rauan Krüger, Rejko Amouri, Rim Weil, Rimona Rajan, Roopa Alcalay, Roy Wu, Ruey-Meei Borgohain, Rupam Sassi, Samia Ben Khachatryan, Samson Bandres-Ciga, Sara El-Sadig, Sarah Wu, Serena Groppa, Sergio Azmin, Shahrul Lim, Shen-Yang Ur-Rehman, Shoaib Ertan, Sibel Stott, Simon Jasaitye, Simona Chowdhury, Sohini Dumanis, Sonya Bardien, Soraya Lubbe, Steven Koks, Sulev Dey, Sumit Xie, Tao Foroud, Tatiana Fon, Ted Beach, Thomas Gasser, Thomas Anderson, Tim Nguyen, Toan Sherer, Todd Schirinzi, Tommaso Shiraishi, Tomotaka Pitcher, Toni Obese, Vida Tumas, Vitor Mohamed, Wael Kamel, Walaa A Luo, Wei Zhou, Xiaopu Zewde, Yared Z Song, Yeajin Wen, Yi Wu, Yihru Joong Kim, Yun Tavadyan, Zaruhi Fang, Zih-Hua AG Heutink The lancet The lancet Lancet Publ. Group London 1474-4422 10.1016/S1474-4422(23)00283-1 English 1015 - 1025 11 22 An understanding of the genetic mechanisms underlying diseases in ancestrally diverse populations is an important step towards development of targeted treatments. Research in African and African admixed populations can enable mapping of complex traits, because of their genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. We aimed to do a comprehensive genome-wide assessment in African and African admixed individuals to better understand the genetic architecture of Parkinson's disease in these underserved populations.We performed a genome-wide association study (GWAS) in people of African and African admixed ancestry with and without Parkinson's disease. Individuals were included from several cohorts that were available as a part of the Global Parkinson's Genetics Program, the International Parkinson's Disease Genomics Consortium Africa, and 23andMe. A diagnosis of Parkinson's disease was confirmed clinically by a movement disorder specialist for every individual in each cohort, except for 23andMe, in which it was self-reported based on clinical diagnosis. We characterised ancestry-specific risk, differential haplotype structure and admixture, coding and structural genetic variation, and enzymatic activity.We included 197 918 individuals (1488 cases and 196 430 controls) in our genome-wide analysis. We identified a novel common risk factor for Parkinson's disease (overall meta-analysis odds ratio for risk of Parkinson's disease 1·58 [95% CI 1·37-1·80], p=2·397 × 10-14) and age at onset at the GBA1 locus, rs3115534-G (age at onset β=-2·00 [SE=0·57], p=0·0005, for African ancestry; and β=-4·15 [0·58], p=0·015, for African admixed ancestry), which was rare in non-African or non-African admixed populations. Downstream short-read and long-read whole-genome sequencing analyses did not reveal any coding or structural variant underlying the GWAS signal. The identified signal seems to be associated with decreased glucocerebrosidase activity.Our study identified a novel genetic risk factor in GBA1 in people of African ancestry, which has not been seen in European populations, and it could be a major mechanistic basis of Parkinson's disease in African populations. This population-specific variant exerts substantial risk on Parkinson's disease as compared with common variation identified through GWAS and it was found to be present in 39% of the cases assessed in this study. This finding highlights the importance of understanding ancestry-specific genetic risk in complex diseases, a particularly crucial point as the Parkinson's disease field moves towards targeted treatments in clinical trials. The distinctive genetics of African populations highlights the need for equitable inclusion of ancestrally diverse groups in future trials, which will be a valuable step towards gaining insights into novel genetic determinants underlying the causes of Parkinson's disease. This finding opens new avenues towards RNA-based and other therapeutic strategies aimed at reducing lifetime risk of Parkinson's disease.The Global Parkinson's Genetics Program, which is funded by the Aligning Science Across Parkinson's initiative, and The Michael J Fox Foundation for Parkinson's Research. PUB:(DE-HGF)16, ; 0, ; Parkinson Disease: ethnology Humans Parkinson Disease: genetics Genome-Wide Association Study Genetic Loci Linkage Disequilibrium Black People: genetics Polymorphism, Single Nucleotide: genetics Genetic Predisposition to Disease: genetics African People: genetics GBA protein, human Journal Article 2023 DZNE-2023-01035 2023 pmc:PMC10593199 pmid:37633302 https://pub.dzne.de/record/265764 https://doi.org/10.1016/S1474-4422(23)00283-1